|
【结 构 式】 
|
【分子编号】41856 【品名】methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate 【CA登记号】88738-78-7 |
【 分 子 式 】C7H9F6O5P 【 分 子 量 】318.1096412 【元素组成】C 26.43% H 2.85% F 35.83% O 25.15% P 9.74% |
合成路线1
该中间体在本合成路线中的序号：(XI)Synthesis of fostriecin: The reduction of tetrahydrofuranone (VI) with DIBAL gives the lactol (VII), which is mesylated with Ms-Cl and treated with TEA to yield the dihydrofuran (VIII). The Sharpless asymmetric dihydroxylation of (VIII) with (DHQD)2AQN affords the diol (IX), which is selectively monosilylated with Tbdms-OTf, providing the silyl ether (X). The condensation of the lactol (X) with phosphonate (XI) by means of KHMDS gives the methyl heptenoate (XII). The silylation of the OH group of (XII) with Tes-OTf yields the disilylated ester (XIII), which is reduced with DIBAL to afford the primary alcohol (XIV). The oxidation of (XIV) with DMP provides the corresponding aldehyde (XV), which is treated with CBr4 and PPH3 to furnish the alpha,alpha-dibromodiene (XVI). Elimination of the Pmb-protecting group of (XVI) with DDQ gives the primary alcohol (XVII), which is treated with Ac2O to yield the acetate (XVIII). The selective monodebromination of (XVIII) with Bu3SnH and Pd(PPh3)4 affords the bromoolefin (XIX), which is condensed with tributylstannane (XX) to provide the adduct (XXI). Cleavage of the acetoxy group of (XXI) by means of DIBAL gives the primary alcohol (XXII).
| 【1】 Boger, D.L.; et al.; Total synthesis of fostriecin (CI-920). J Am Chem Soc 2001, 123, 18, 4161. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 49640 | (5R)-5-[[(4-methoxybenzyl)oxy]methyl]dihydro-2(3H)-furanone | C13H16O4 | 详情 | 详情 | |
| (VII) | 49641 | (5R)-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydro-2-furanol | C13H18O4 | 详情 | 详情 | |
| (VIII) | 49642 | (2R)-2-[[(4-methoxybenzyl)oxy]methyl]-2,3-dihydrofuran; 4-[[(2R)-2,3-dihydro-2-furanylmethoxy]methyl]phenyl methyl ether | C13H16O3 | 详情 | 详情 | |
| (IX) | 49643 | (3R,5R)-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydro-2,3-furandiol | C13H18O5 | 详情 | 详情 | |
| (X) | 49644 | (3R,5R)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-[[(4-methoxybenzyl)oxy]methyl]tetrahydro-2-furanol | C19H32O5Si | 详情 | 详情 | |
| (XI) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (XII) | 49645 | methyl (Z,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-7-[(4-methoxybenzyl)oxy]-2-heptenoate | C22H36O6Si | 详情 | 详情 | |
| (XIII) | 49646 | methyl (Z,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-6-[(triethylsilyl)oxy]-2-heptenoate | C28H50O6Si2 | 详情 | 详情 | |
| (XIV) | 49647 | (Z,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-6-[(triethylsilyl)oxy]-2-hepten-1-ol | C27H50O5Si2 | 详情 | 详情 | |
| (XV) | 49648 | (Z,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-6-[(triethylsilyl)oxy]-2-heptenal | C27H48O5Si2 | 详情 | 详情 | |
| (XVI) | 49649 | (5R,7R)-5-[(1Z)-4,4-dibromo-1,3-butadienyl]-9,9-diethyl-7-[[(4-methoxybenzyl)oxy]methyl]-2,2,3,3-tetramethyl-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (1R,2Z)-5,5-dibromo-1-[(2R)-3-[(4-methoxybenzyl)oxy]-2-[(triethylsilyl)oxy]propyl]-2,4-pentadienyl ether | C28H48Br2O4Si2 | 详情 | 详情 | |
| (XVII) | 49650 | (2R,4R,5Z)-8,8-dibromo-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(triethylsilyl)oxy]-5,7-octadien-1-ol | C20H40Br2O3Si2 | 详情 | 详情 | |
| (XVIII) | 49651 | (2R,4R,5Z)-8,8-dibromo-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(triethylsilyl)oxy]-5,7-octadienyl acetate | C22H42Br2O4Si2 | 详情 | 详情 | |
| (XIX) | 49652 | (2R,4R,5Z,7Z)-8-bromo-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(triethylsilyl)oxy]-5,7-octadienyl acetate | C22H43BrO4Si2 | 详情 | 详情 | |
| (XX) | 49653 | tert-butyl(diphenyl)[[(E)-3-(tributylstannyl)-2-propenyl]oxy]silane; tert-butyl(diphenyl)silyl (E)-3-(tributylstannyl)-2-propenyl ether | C31H50OSiSn | 详情 | 详情 | |
| (XXI) | 49654 | (2R,4R,5Z,7Z,9E)-4-[[tert-butyl(dimethyl)silyl]oxy]-11-[[tert-butyl(diphenyl)silyl]oxy]-2-[(triethylsilyl)oxy]-5,7,9-undecatrienyl acetate | C41H66O5Si3 | 详情 | 详情 | |
| (XXII) | 49655 | (2R,4R,5Z,7Z,9E)-4-[[tert-butyl(dimethyl)silyl]oxy]-11-[[tert-butyl(diphenyl)silyl]oxy]-2-[(triethylsilyl)oxy]-5,7,9-undecatrien-1-ol | C39H64O4Si3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The intermediate stannane derivative (XVI) has been obtained as follows: The esterification of propynoic acid (XII) with diphenyldiazomethane (XIII) in benzene gives the corresponding ester (XIV), which is then condensed with Me3Sn-Cu(CN)Li (XV) in THF/methanol to yield the desired intermediate (XVI). 3-Hydroxy-2(S)-methylpropionic acid methyl ester (I) is converted into the chiral tosylate (II) by conventional methods. The condensation of (II) with 4-pentenylmagnesium bromide (III) in THF gives the chiral tetrahydropyranyl ether (IV), which is condensed with the phosphonate (V) by means of KHMDS in THF/toluene yielding the chiral nonenoic ester (VI). The reduction of (VI) with DIBAL in the same solvent, followed by protection of the resulting alcohol with TBDPSCl and TEA in dichloromethane affords the protected diol (VII). The selective elimination of the THP protecting group, followed by reaction with TsCl and TEA in dichloromethane affords the tosylate (VIII), which is condensed with lithium acetylide (IX) in DMSO to provide the terminal acetylene (X). The deprotection of (X) with TBAF, followed by reaction with Me3Al, Cp2ZrCl2, and I2 in THF gives the omega iodoundecadienol (XI), which is condensed with the stannane derivative (XVI) by means of PdCl2 in DMF yielding the tetradecatrienoic diphenylmethyl ester (XVII). The chiral epoxidation of (XVII) with Ti(OiPr)4, BuOOH and (R,R)(+)-diisopropyl tartrate (DIPT) in dichloroethane affords the hydroxymethyl-oxirane (XVIII), which is oxidized with tetrapropylammonium perruthenate (TPAP) to provide the oxirane carbaldehyde (XIX).
| 【1】 Bates, R.W.; et al.; Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (Pi-allyl)tricarbonyliron lactone complex. J Chem Soc - Perkins Trans I 1999, 14, 1917. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 41854 | (2S)-2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl 4-methylbenzenesulfonate | C17H26O5S | 详情 | 详情 | |
| (III) | 39424 | bromo(4-pentenyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (IV) | 41855 | (3R)-3-methyl-8-nonenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(3R)-3-methyl-8-nonenyl]oxy]tetrahydro-2H-pyran | C15H28O2 | 详情 | 详情 | |
| (V) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (VI) | 41857 | methyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenoate | C17H30O4 | 详情 | 详情 | |
| (VII) | 41858 | tert-butyl[[(Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl ether | C32H48O3Si | 详情 | 详情 | |
| (VIII) | 41859 | (2R,7Z)-9-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-7-nonenyl 4-methylbenzenesulfonate | C33H44O4SSi | 详情 | 详情 | |
| (IX) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (X) | 41860 | tert-butyl[[(Z,8R)-8-methyl-2-undecen-10-ynyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-2-undecen-10-ynyl ether | C28H38OSi | 详情 | 详情 | |
| (XI) | 41861 | (2Z,8R,10E)-11-iodo-8,10-dimethyl-2,10-undecadien-1-ol | C13H23IO | 详情 | 详情 | |
| (XII) | 10398 | 2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether | C13H19IO2 | 详情 | 详情 | |
| (XIII) | 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | |
| (XIV) | 41862 | benzhydryl 2-butynoate | C17H14O2 | 详情 | 详情 | |
| (XVI) | 41863 | benzhydryl (E)-3-(trimethylstannyl)-2-butenoate | C20H24O2Sn | 详情 | 详情 | |
| (XVII) | 41864 | benzhydryl (2E,4E,7R,12Z)-14-hydroxy-3,5,7-trimethyl-2,4,12-tetradecatrienoate | C30H38O3 | 详情 | 详情 | |
| (XVIII) | 41865 | benzhydryl (2E,4E,7R)-11-[(2R,3S)-3-(hydroxymethyl)oxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H38O4 | 详情 | 详情 | |
| (XIX) | 41866 | benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-formyloxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H36O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXVII)The target compound has been obtained as follows: The condensation of ester intermediate (XI) with aldehyde intermediate (XXI) by means of lithium 2,2,6,6-tetramethylpiperidide (Li-TMP) gives the addition compound (XXXI), which is reduced at the ester group with LiAlH4, yielding the carbinol (XXXII). The reduction of this carbinol by sulfonation with mesitylenesulfonyl chloride, followed by reduction with LiAlH4, affords the corresponding methyl derivative (XXXIII), which is silylated at the secondary OH group with TBDMS-Otf, providing the fully protected compound (XXXIV). Elimination of the Pmb protecting groups of (XXXIV) with DDQ yields the diol (XXXV), which is selectively oxidized at the primary OH group to the corresponding aldehyde (XXXVI) by means of TEMPO. The Wittig condensation of (XXXVI) with phosphonate (XXXVII) by means of K2CO3 and 18-C-6 affords the octadecatetraenoic ester (XXXVIII), which is treated with trichloroacetyl isocyanate and K2CO3 to provide the carbamate (XXXIX). The reduction of the ester group of (XXXIX) by means of DIBAL gives the primary alcohol (XL), which is finally oxidized with DMP to the expected intermediate aldehyde (XLI).
| 【1】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377. |
| 【2】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XXI) | 42632 | (2R,3S,4S,5Z)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-5,7-octadienal | C18H24O3 | 详情 | 详情 | |
| (XXXI) | 42641 | 2,6-dimethylphenyl (2S,3S,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-3-hydroxy-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadienoate | C52H76O8Si | 详情 | 详情 | |
| (XXXII) | 42642 | (2R,3R,4S,5S,6S,7Z)-2-[(Z,4S,5R,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-2-heptenyl]-5-[(4-methoxybenzyl)oxy]-4,6-dimethyl-7,9-decadiene-1,3-diol | C44H70O7Si | 详情 | 详情 | |
| (XXXIII) | 42643 | (3Z,5S,6S,7S,8R,9S,11Z,13S,14R,15S)-14-[[tert-butyl(dimethyl)silyl]oxy]-6,16-bis[(4-methoxybenzyl)oxy]-5,7,9,11,13,15-hexamethyl-1,3,11-hexadecatrien-8-ol | C44H70O6Si | 详情 | 详情 | |
| (XXXIV) | 42644 | (5R,6S,7Z,10S,11R)-11-[(1R,2S,3S,4Z)-2-[(4-methoxybenzyl)oxy]-1,3-dimethyl-4,6-heptadienyl]-5-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,8,10,13,13,14,14-undecamethyl-4,12-dioxa-3,13-disila-7-pentadecene; (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-[(4-methoxybenzyl)oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienyl 4-methoxybenzyl ether | n/a | C50H84O6Si2 | 详情 | 详情 |
| (XXXV) | 42645 | (2S,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatriene-1,11-diol | n/a | C34H68O4Si2 | 详情 | 详情 |
| (XXXVI) | 42646 | (2R,3R,4S,5Z,8S,9R,10R,11S,12S,13Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-5,13,15-hexadecatrienal | n/a | C34H66O4Si2 | 详情 | 详情 |
| (XXXVII) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (XXXVIII) | 42647 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C37H70O5Si2 | 详情 | 详情 |
| (XXXIX) | 42648 | methyl (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7,15,17-octadecatetraenoate | n/a | C38H71NO6Si2 | 详情 | 详情 |
| (XL) | 42649 | (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-13-hydroxy-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-6,11-tridecadienyl carbamate | C37H71NO5Si2 | 详情 | 详情 | |
| (XLI) | 42650 | (1S,2R,3R,4S,6Z,8S,9S,10S,11Z)-3,9-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4,6,8,10-pentamethyl-1-[(1S,2Z)-1-methyl-2,4-pentadienyl]-13-oxo-6,11-tridecadienyl carbamate | C37H69NO5Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXVII)The oxidation of the primary alcohol of (XIX) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XX), which is condensed with (Z,Z)-2,4-heptadienamide (XXI) by means of Tms-OTf in dichloroethane to yield the N,N-acylated aminal (XXII). This compound undergoes elimination when treated with NaH in hot trifluoromethylbenzene affording enamide (XXIII) as a mixture of (Z) and (E) isomers, which is treated with TBAF in THF undergoing elimination of the Tips protecting group only and providing the monosilylated compound (XXIV). Removal of the remaining silyl group requires more drastic conditions (TBAF in THF/HMPA) that cause isomerization of the enamide double bond yielding a mixture of the target compound Salicylhalamide A along with its isomer Salicylhalamide B that are separated by HPLC chromatography. The intermediate (Z,Z)-2,4-heptadienamide (XXI) has been obtained as follows: The oxidation of (Z)-2-penten-1-ol (XXV) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XXVI), which is condensed with phosphonate (XXVII) by means of KH in THF to yield methyl (Z,Z)-2,4-heptadienoate (XXVIII). The hydrolysis of (XXVIII) with Ba(OH)2 in methanol/water affords (Z,Z)-2,4-heptadienoic acid (XXIX), which is finally treated with ethyl chloroformate and ammonia to provide the target amide (XXI).
| 【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 47502 | (2Z,4Z)-N-((E)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide | C51H71NO5Si2 | 详情 | 详情 | |
| (XXIIIb) | 47503 | (2Z,4Z)-N-((Z)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide | C51H71NO5Si2 | 详情 | 详情 | |
| (XXIVa) | 47504 | (2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide | C42H51NO5Si | 详情 | 详情 | |
| (XXIVb) | 47505 | (2Z,4Z)-N-[(Z)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide | C42H51NO5Si | 详情 | 详情 | |
| (XIX) | 47494 | (3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one | C35H44O5Si | 详情 | 详情 | |
| (XX) | 47500 | C44H62O5Si2 | 详情 | 详情 | ||
| (XXI) | 47499 | (2Z,4Z)-2,4-heptadienamide | C7H11NO | 详情 | 详情 | |
| (XXII) | 47501 | (2Z,4Z)-N-[3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-[(2Z,4Z)-2,4-heptadienoylamino]propyl]-2,4-heptadienamide | C58H82N2O6Si2 | 详情 | 详情 | |
| (XXV) | 47495 | cis-2-pentenol; (Z)-2-penten-1-ol | 1576-95-0 | C5H10O | 详情 | 详情 |
| (XXVI) | 47496 | (Z)-2-pentenal | C5H8O | 详情 | 详情 | |
| (XXVII) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (XXVIII) | 47497 | methyl (2Z,4Z)-2,4-heptadienoate | C8H12O2 | 详情 | 详情 | |
| (XXIX) | 47498 | (2Z,4Z)-2,4-heptadienoic acid | C7H10O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXVII)The oxidation of the primary alcohol of (XIX) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XX), which is condensed with (Z,Z)-2,4-heptadienamide (XXI) by means of Tms-OTf in dichloroethane to yield the N,N-acylated aminal (XXII). This compound undergoes elimination when treated with NaH in hot trifluoromethylbenzene affording enamide (XXIII) as a mixture of (Z) and (E) isomers, which is treated with TBAF in THF undergoing elimination of the Tips protecting group only and providing the monosilylated compound (XXIV). Removal of the remaining silyl group requires more drastic conditions (TBAF in THF/HMPA) that cause isomerization of the enamide double bond yielding a mixture of the target compound Salicylhalamide A along with its isomer Salicylhalamide B that are separated by HPLC chromatography. The intermediate (Z,Z)-2,4-heptadienamide (XXI) has been obtained as follows: The oxidation of (Z)-2-penten-1-ol (XXV) with TPAP and NMO in dichloromethane gives the corresponding aldehyde (XXVI), which is condensed with phosphonate (XXVII) by means of KH in THF to yield methyl (Z,Z)-2,4-heptadienoate (XXVIII). The hydrolysis of (XXVIII) with Ba(OH)2 in methanol/water affords (Z,Z)-2,4-heptadienoic acid (XXIX), which is finally treated with ethyl chloroformate and ammonia to provide the target amide (XXI).
| 【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIIIa) | 47502 | (2Z,4Z)-N-((E)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide | C51H71NO5Si2 | 详情 | 详情 | |
| (XXIIIb) | 47503 | (2Z,4Z)-N-((Z)-3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-propenyl)-2,4-heptadienamide | C51H71NO5Si2 | 详情 | 详情 | |
| (XXIVa) | 47504 | (2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide | C42H51NO5Si | 详情 | 详情 | |
| (XXIVb) | 47505 | (2Z,4Z)-N-[(Z)-3-((3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide | C42H51NO5Si | 详情 | 详情 | |
| (XIX) | 47494 | (3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one | C35H44O5Si | 详情 | 详情 | |
| (XX) | 47500 | C44H62O5Si2 | 详情 | 详情 | ||
| (XXI) | 47499 | (2Z,4Z)-2,4-heptadienamide | C7H11NO | 详情 | 详情 | |
| (XXII) | 47501 | (2Z,4Z)-N-[3-[(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-6-methyl-1-oxo-14-[(triisopropylsilyl)oxy]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl]-1-[(2Z,4Z)-2,4-heptadienoylamino]propyl]-2,4-heptadienamide | C58H82N2O6Si2 | 详情 | 详情 | |
| (XXV) | 47495 | cis-2-pentenol; (Z)-2-penten-1-ol | 1576-95-0 | C5H10O | 详情 | 详情 |
| (XXVI) | 47496 | (Z)-2-pentenal | C5H8O | 详情 | 详情 | |
| (XXVII) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (XXVIII) | 47497 | methyl (2Z,4Z)-2,4-heptadienoate | C8H12O2 | 详情 | 详情 | |
| (XXIX) | 47498 | (2Z,4Z)-2,4-heptadienoic acid | C7H10O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The butenoic ester intermediate (VIII) has been obtained as follows: The condensation of the known aldehyde (I) with phosphonate (II) by means of KHMDS in THF gives the unsaturated ester (III), which is selectively hydrolyzed at its benzoate group by means of K2CO3 in methanol to yield the ethanol derivative (IV). The oxidation of (IV) by means of DMP affords the acetaldehyde (V), which is condensed with the phosphorane (VI) by means of DBU and LiCl in acetonitrile to provide the methyl ketone (VII) (1). Finally, this compound is methylated by means of Me2Zn and Ni(acac)2 in ethyl ether to give the target butenoic ester intermediate (VIII)
| 【1】 Paterson, I.; et al.; Total synthesis of the microtubule-stabilizing agent (-)-laulimalide. Org Lett 2001, 3, 20, 3149. |
| 【2】 Paterson, I.; et al.; Synthesis of the macrocyclic core of laulimalide. Org Lett 2001, 3, 2, 213. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 61164 | 2-[(2S,6R)-6-(2-oxoethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl benzoate | C16H18O4 | 详情 | 详情 | |
| (II) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (III) | 61165 | 2-{(2S,6R)-6-[(Z)-4-methoxy-4-oxo-2-butenyl]-3,6-dihydro-2H-pyran-2-yl}ethyl benzoate | C19H22O5 | 详情 | 详情 | |
| (IV) | 61166 | methyl (Z)-4-[(2R,6S)-6-(2-hydroxyethyl)-5,6-dihydro-2H-pyran-2-yl]-2-butenoate | C12H18O4 | 详情 | 详情 | |
| (V) | 59559 | Dimethyl acetonylphosphonate; Acetylmethylphosphonic acid dimethyl ester; Dimethyl (2-oxopropyl)phosphonate | 4202-14-6 | C5H11O4P | 详情 | 详情 |
| (VI) | 61167 | methyl (Z)-4-[(2R,6S)-6-(2-oxoethyl)-5,6-dihydro-2H-pyran-2-yl]-2-butenoate | C12H16O4 | 详情 | 详情 | |
| (VII) | 61168 | methyl (Z)-4-{(2R,6S)-6-[(E)-4-oxo-2-pentenyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate | C15H20O4 | 详情 | 详情 | |
| (VIII) | 61169 | methyl (Z)-4-{(2R,6R)-6-[(2R)-2-methyl-4-oxopentyl]-5,6-dihydro-2H-pyran-2-yl}-2-butenoate | C16H24O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)The title prostaglandin derivative was synthesized by two methods. The benzoate ester group of the known lactone precursor (I) was removed by methanolysis in the presence of K2CO3 to afford diol (II), which was further protected as the bis-tetrahydropyranyl ether (III). Catalytic hydrogenation of (III) provided the 13,14-dihydro compound (IV). The lactone function of (IV) was then reduced with LiAlH4 to the corresponding open chain diol, which was subsequently protected as the bis-silyl derivative (V). Regioselective Swern oxidation of the silylated primary hydroxyl of (V) furnished aldehyde (VI). This was subjected to Wadsworth-Emmons olefination with phosphonate (VII) in the presence of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) as the K+-complexing agent to yield the Z-unsaturated ester (VIII) as the major isomer. Ester group reduction in (VIII) by means of DIBAL, followed by desilylation with tetrabutylammonium fluoride, provided the allylic alcohol (IX).
| 【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 56280 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C23H28O5 | 详情 | 详情 | |
| (II) | 56281 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one | C16H24O4 | 详情 | 详情 | |
| (III) | 56282 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C26H40O6 | 详情 | 详情 | |
| (IV) | 56283 | (3aR,4R,5R,6aS)-4-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C26H42O6 | 详情 | 详情 | |
| (V) | 56284 | {(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methyl triethylsilyl ether; ({(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methoxy)(triethyl)silane | C37H72O6Si2 | 详情 | 详情 | |
| (VI) | 56285 | (1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentanecarbaldehyde | C31H56O6Si | 详情 | 详情 | |
| (VII) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (VIII) | 56286 | methyl (Z)-4-{(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}-2-butenoate | C35H62O7Si | 详情 | 详情 | |
| (IX) | 56287 | (1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol | C28H48O6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)The benzoate ester group of the known lactone precursor (I) was removed by methanolysis in the presence of K2CO3 to afford diol (II), which was further protected as the bis-tetrahydropyranyl ether (III). Catalytic hydrogenation of (III) provided the 13,14-dihydro compound (IV). The lactone function of (IV) was then reduced with LiAlH4 to the corresponding open chain diol, which was subsequently protected as the bis-silyl derivative (V). Regioselective Swern oxidation of the silylated primary hydroxyl of (V) furnished aldehyde (VI). This was subjected to Wadsworth-Emmons olefination with phosphonate (VII) in the presence of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) as the K+-complexing agent to yield the Z-unsaturated ester (VIII) as the major isomer. Ester group reduction in (VIII) by means of DIBAL, followed by desilylation with tetrabutylammonium fluoride, provided the allylic alcohol (IX).
| 【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 56280 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C23H28O5 | 详情 | 详情 | |
| (II) | 56281 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one | C16H24O4 | 详情 | 详情 | |
| (III) | 56282 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C26H40O6 | 详情 | 详情 | |
| (IV) | 56283 | (3aR,4R,5R,6aS)-4-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C26H42O6 | 详情 | 详情 | |
| (V) | 56284 | {(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methyl triethylsilyl ether; ({(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methoxy)(triethyl)silane | C37H72O6Si2 | 详情 | 详情 | |
| (VI) | 56285 | (1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentanecarbaldehyde | C31H56O6Si | 详情 | 详情 | |
| (VII) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (VIII) | 56286 | methyl (Z)-4-{(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}-2-butenoate | C35H62O7Si | 详情 | 详情 | |
| (IX) | 56287 | (1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol | C28H48O6 | 详情 | 详情 |